Matrix adhering to nasal mucosa

ABSTRACT

This invention provides a matrix adhering to the nasal mucosa which allows improved transfer into the brain of a drug exerting its effect in the brain and is capable of continuously supplying the drug into the brain. This matrix contains a polyglycerol fatty acid ester, the drug exerting its effect in the brain, and a viscogenic substance.

This application is a 371 of PCT/JP00/05739 filed Aug. 25, 2000.

TECHNICAL FIELD

The present invention relates to a matrix adhering to the nasal mucosa,which allows improved transfer, into the brain, of a drug exerting itseffect in the brain and is capable of continuously supplying the druginto the brain.

BACKGROUND ART

As those literatures that disclose pharmaceutical compositions adsorbedinto mucosae, the followings are known.

1) WO-A 98/42323 describes “A pharmaceutical composition comprising anunease inhibitor and an oil base material”, and there is an example ofan agent adhering to mucosae on digestive tracts.

2) JP-A 5-132416 describes “A matrix adhering to mucosae on digestivetracts and being solid at ordinary temperature, wherein a materialrendered viscous with water is dispersed in the vicinity of at leastsurface layers of matrix particles containing a polyglycerol fatty acidester or lipid and an active ingredient”.

3) JP-A 10-324643 describes “A pharmaceutical composition adhering tomucosae on digestive tracts, which comprises a swelling agent for amaterial rendered viscous with water”.

On the other hand, as those literatures that disclose pharmaceuticalcompositions adhering to the nasal mucosa, the followings are known.

4) JP-A 56-100714 describes “A preparation adhering to mucosae on theoral or nasal cavity, wherein a drug layer comprising an ointment basematerial containing a drug and a surfactant is unevenly distributed in amucosa-adhesive coating layer consisting of a cellulose ether and/or anacrylate polymer or a pharmaceutically acceptable salt thereof.”

5) JP-A 7-316038 describes “A pharmaceutical composition foradministration into mucosae, which comprises a) an acrylic acid-alkyl(meth)acrylate copolymer or a salt thereof, b) an alkali metal saltand/or an alkaline earth metal salt, c) a drug and d) water as essentialingredients.”

6) JP-A 7-215843 discloses “A sustained release pharmacologicalcomposition adhering to biological tissues, which comprises a largenumber of micro-units containing at least one active ingredient and ameans of regulating release of said active ingredient, wherein themicro-units do substantially not show biological adhesion before coatingthereof, the respective micro-units are coated with a biologicallyadhering polymeric coating, the coating contains one or more physicallyacceptable polymers, at least one of the polymers is a biologicallyadhering polymer, and said coating endows the micro-units with anability to adhere to biological tissues.”

7) U.S. Pat. No. 5,723,143 describes “A solid therapeutic or hygieniccomposition adhering to mucosae, which is used in administration intooral or nasal mucosae.”

8) WO-A 95/5163 describes “An emulsion adhering to the living body,which is useful as a pharmaceutical composition with enhanced transferof a drug into mucosae on the living body.”

When a drug exerting its action on the brain is administered into theliving body, transfer of the drug into the brain is significantlyrestricted by the blood-brain barrier. Accordingly, there is demand fora preparation capable of allowing a drug exerting its effect in thebrain to exert the effect sufficiently in the brain.

DISCLOSURE OF THE INVENTION

The present inventors made extensive study for allowing a drug exertingits effect in the brain to exert the effect sufficiently in the brain,and as a result, they unexpectedly found for the first time that when amatrix comprising a polyglycerol fatty acid ester, said drug and aviscogenic substance was created, said matrix had excellent propertiesas a pharmaceutical preparation, for example excellent adhesion to thenasal mucosa, improved transfer of said drug into the brain, sustainedsupply of the drug into the brain, etc., and on the basis of thisfinding, this invention was completed.

That is, this invention relates to:

(1) a matrix adhering to the nasal mucosa which allows improved transferinto the brain of a drug exerting its effect in the brain, whichcomprises a polyglycerol fatty acid ester, the drug exerting its effectin the brain, and a viscogenic substance;

(2) the matrix according to the above-mentioned (1), wherein thepolyglycerol fatty acid ester is an ester of a polyglycerol having apolymerization degree of 2 to 20 with a fatty acid having 12 to 22carbon atoms;

(3) the matrix according to the above-mentioned (1), wherein the HLB ofthe polyglycerol fatty acid ester is 1 to 9;

(4) the matrix according to the above-mentioned (1), which comprisesabout 40 to about 95% by weight of the polyglycerol fatty acid ester;

(5) the matrix according to the above-mentioned (1), wherein theviscogenic substance is an acrylate type polymer or a salt thereof;

(6) the matrix according to the above-mentioned (5), wherein themolecular weight of the acrylate type polymer or a salt thereof is1,000,000 to 6,000,000;

(7) the matrix according to the above-mentioned (1), which comprisesabout 4 to about 30% by weight of the viscogenic substance;

(8) the matrix according to the above-mentioned (1), which furthercomprises a swelling agent for the viscogenic substance;

(9) the matrix according to the above-mentioned (8), wherein theswelling agent for the viscogenic substance is curdlan and/orlow-substituted hydroxypropylmethyl cellulose;

(10) the matrix according to the above-mentioned (1), which furthercomprises lipid;

(11) the matrix according to the above-mentioned (1), wherein the drugexerting its effect in the brain is a drug hardly transferring into thebrain;

(12) the matrix according to the above-mentioned (1), wherein the drugexerting its effect in the brain is a sedative-hypnotic agent, ananti-anxiety agent, an antidepressant agent or an agent for treatingAlzheimer's disease;

(13) the matrix according to the above-mentioned (1), wherein the drugexerting its effect in the brain is a compound having a melatoninreceptor antagonist action;

(14) the matrix according to the above-mentioned (1),

wherein the drug exerting its effect in the brain is a compoundrepresented by the formula:

wherein R¹ is a hydrocarbon group which may have a substituent group, anamino group which may have a substituent group or a heterocyclic groupwhich may have a substituent group,

R² is a hydrogen atom or a hydrocarbon group which may have asubstituent group,

R³ is a hydrogen atom or a hydrocarbon group which may have asubstituent group or a heterocyclic group which may have a substituentgroup,

X is CHR⁴, NR⁴, O or S whereupon R⁴ represents a hydrogen atom or ahydrocarbon group which may have a substituent group,

Y is C, CH or N provided that when X represents CH₂, Y is C or CH,

is a single or double bond,

ring A is a 5- to 7-memberred, oxygen atom-containing heterocyclic ringwhich may have a substituent group,

ring B is a benzene ring which may have a substituent group, and

m is an integer of 1 to 4; or a salt thereof;

(15) the matrix according to the above-mentioned (1), wherein the drugexerting its effect in the brain is(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide;

(16) the matrix according to the above-mentioned (1), wherein the drugexerting its effect in the brain is(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]acetamide;

(17) the matrix according to the above-mentioned (1), which comprisesabout 0.1 to about 50% by weight of the drug exerting its effect in thebrain;

(18) a solid preparation comprising the matrix described in theabove-mentioned (1);

(19) the solid preparation according to the above-mentioned (18), whichis finely divided particles or powder;

(20) the solid preparation according to the above-mentioned (19), whichis spherical;

(21) the solid preparation according to the above-mentioned (19), whichhas a particle diameter of about 0.1 to about 100 μm;

(22) a method of improving transfer, into the brain, of a drug exertingits effect in the brain, which comprises using a matrix comprising apolyglycerol fatty acid ester, said drug and a viscogenic substance; and

(23) use of a polyglycerol fatty acid ester, a drug exerting its effectin the brain, and a viscogenic substance in producing a matrix adheringto the nasal mucosa which allows improved transfer of said drug into thebrain.

In this invention, the polyglycerol fatty acid ester may be any one ofmonoesters, diesters and polyesters insofar as they are esters ofpolyglycerols with fatty acids. The polyglycerol fatty acid ester ischaracterized in that it does not show crystalline polymorphism andhardly interacts with a drug so that even if the drug is coexistenttherewith, the drug is hardly inactivated and is thus stable for aprolonged period of time.

The polyglycerol is “a polyvalent alcohol having “n” (cyclic) to “n+2”(linear or branched) hydroxyl groups and “n−1” (linear or branched) to“n” (cyclic) ether linkages in one molecule” (“Polyglycerol Ester”edited by Sakamoto Yakuhin Kogyo Co., Ltd. and published on Oct. 4,1994), and may be linear or branched. As the polyglycerol, use can bemade of e.g. those compounds represented by:

wherein n, degree of polymerization, is an integer of 2 or more. n isusually 2 to 50, preferably 2 to 20 and more preferably 2 to 10.Examples of such polyglycerols include diglycerol, triglycerol,tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol,nonaglycerol, decaglycerol, pentadecaglycerol, eicosaglycerol,triacontaglycerol etc. Among these polyglycerols, for exampletetraglycerol, hexaglycerol, decaglycerol etc. are preferable.

As the fatty acid, for example fatty acids each containing 8 to 40carbon atoms, preferably 12 to 22 carbon atoms, are exemplified. Thefatty acid may be saturated or unsaturated, and includes e.g. palmiticacid, stearic acid, oleic acid, linolic acid, linolenic acid, myristicacid, lauric acid, ricinoleic acid, caprylic acid, capric acid, behenicacid etc. Among these, e.g. stearic acid, oleic acid, lauric acid,linolic acid, behenic acid etc. are preferable.

Examples of the polyglycerol fatty acid ester include e.g. behenic acidhexa(tetra)glyceride, behenic acid dodeca(deca)glyceride, behenic acidocta(hexa)glyceride, caprylic acid mono(deca)glyceride, caprylic aciddi(tri)glyceride, capric acid di(tri)glyceride, lauric acidmono(tetra)glyceride, lauric acid mono(hexa)glyceride, lauric acidmono(deca)glyceride, oleic acid mono(tetra)glyceride, oleic acidmono(hexa)glyceride, oleic acid mono(deca)glyceride, oleic aciddi(tri)glyceride, oleic acid di(tetra)glyceride, oleic acidsesqui(deca)glyceride, oleic acid penta(tetra)glyceride, oleic acidpenta(hexa)glyceride, oleic acid deca(deca)glyceride, linolic acidmono(hepta)glyceride, linolic acid di(tri)glyceride, linolic aciddi(tetra)glyceride, linolic acid di(hexa)glyceride, stearic acidmono(di)glyceride, stearic acid mono(tetra)glyceride, stearic acidmono(hexa)glyceride, stearic acid mono(deca)glyceride, stearic acidtri(tetra)glyceride, stearic acid tri(hexa)glyceride, stearic acidsesqui(hexa)glyceride, stearic acid penta(tetra)glyceride, stearic acidpenta(hexa)glyceride, stearic acid deca(deca)glyceride, palmitic acidmono(tetra)glyceride, palmitic acid mono(hexa)glyceride, palmitic acidmono(deca)glyceride, palmitic acid tri(tetra)glyceride, palmitic acidtri(hexa)glyceride, palmitic acid sesqui(hexa)glyceride, palmitic acidpenta(tetra)glyceride, palmitic acid penta(hexa)glyceride, palmitic aciddeca(deca)glyceride etc. One or more, preferably two or three of theabove polyglycerol fatty acid esters may be mixed and used in anarbitrary ratio.

The molecular weight of the polyglycerol fatty acid ester is usuallyabout 200 to about 7000, preferably about 300 to about 3000 and morepreferably about 500 to about 3000.

The HLB (hydrophile-lipophile balance) of the polyglycerol fatty acidester is usually 1 to 22, preferably 1 to 15 and more preferably 1 to 9.The HLB may be adjusted as desired by suitably mixing two or morepolyglycerol fatty acid esters which are different in HLB. By adjustingthe HLB of the polyglycerol fatty acid ester, the releasability anddissolution of the drug can be controlled.

Although the melting point of the polyglycerol fatty acid ester is alsovaried depending on the type of the drug and the viscogenic substance,the melting point is e.g. about 15 to about 80° C., preferably about 30to about 75° C. and more preferably about 45 to about 75° C.

The polyglycerol fatty acid ester usually used in this invention issolid at ordinary temperature (15° C.), but insofar as the matrixadhering to the nasal mucosa is solid at ordinary temperature, apolyglycerol fatty acid ester which is liquid at ordinary temperaturemay also be used.

The polyglycerol fatty acid ester is preferably an ester of apolyglycerol having a polymerization degree of 2 to 20 with a fatty acidhaving 12 to 22 carbon atoms.

Preferable examples of the polyglycerol fatty acid ester include e.g.behenic acid hexa(tetra)glyceride (for example, trade name: Poem J-46Bproduced by Riken Vitamin Co., Ltd.; trade name: HB-310 produced bySakamoto Yakuhin Kogyo, etc.), behenic acid dodeca(deca)glyceride (forexample, trade name: OB-500 produced by Sakamoto Yakuhin Kogyo Co.,Ltd., etc.), behenic acid octa(hexa)glyceride (for example, trade name:DB-750 produced by Sakamoto Yakuhin Kogyo Co., Ltd., etc.), stearic acidpenta(tetra)glyceride (for example, trade name: PS-310 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), stearic acidmono(tetra)glyceride (for example, trade name: MS-310 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), stearic acidpenta(hexa)glyceride (for example, trade name: PS-500 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), stearic acidsesqui(hexa)glyceride (for example, trade name: SS-500 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), stearic aciddeca(deca)glyceride (for example, trade name: DAS-750 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), stearic acidmono(hexa)glyceride (for example, trade name: PO-500 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), oleic acidpenta(tetra)glyceride (for example, trade name: PO-310 produced bySakamoto Yakuhin Kogyo Co., Ltd., etc.), oleic acid deca(deca)glyceride(for example, trade name: DAO-750 produced by Sakamoto Yakuhin KogyoCo., Ltd., etc.), stearic acid mono(deca)glyceride,polyglycerol-condensed ricinoleic acid ester [polyglycerolpolyricinolate, for example, tetraglycerol polyricinolate (for example,trade name: CRS-75 produced by Sakamoto Yakuhin Kogyo Co., Ltd., etc.)]or the like. Two or more, preferably two or three of the abovepolyglycerol fatty acid esters may be mixed and used in an arbitraryratio.

The content of the polyglycerol fatty acid ester in the matrix adheringto the nasal mucosa is for example about 5 to about 98% by weight,preferably about 20 to about 95% by weight and more preferably about 40to about 95% by weight.

The polyglycerol fatty acid ester is used in an amount of about 0.01 toabout 10000 parts by weight, preferably about 0.1 to about 1000 parts byweight, relative to 1 part by weight of the drug exerting its effect inthe brain.

The matrix adhering to the nasal mucosa according to this invention mayfurther contain lipid. Use is made of lipid having a melting point ofabout 40 to about 120° C., preferably about 40 to about 90° C. The lipidinclude e.g. C₁₄₋₂₂ saturated fatty acids (for example, myristic acid,palmitic acid, stearic acid, behenic acid etc.) or salts thereof (forexample, sodium salts, potassium salts); C₁₆₋₂₂ higher alcohols (forexample, cetyl alcohol, stearyl alcohol etc.); fatty acid glycerolesters, that is, monoglycerides, diglycerides and triglycerides with theabove fatty acids (for example, 1-monostearin, 1-monopalmitin etc.);fats and oils (for example, soybean oil, olive oil, rapeseed oil,peppermint oil, sesame oil, castor oil, camellia oil, wheat malt oil,fennel oil, corn oil, sunflower oil, cottonseed oil, coconut oil, peanutoil and hardened oils thereof, tallow, lard etc.); wax (for example,beeswax, carnauba wax, spermaceti, white wax etc.); hydrocarbons (forexample, paraffin, microcrystalline wax etc.); phospholipid (forexample, hydrogenated lecithin etc.), etc. Among these lipids, forexample fats and oils, wax, C₁₄₋₂₂ saturated fatty acids, C₁₆₋₂₂ higheralcohols, hydrocarbons etc. are preferable, and hardened cottonseed oil,hardened castor oil, hardened soybean oil, carnauba wax, stearic acid,stearyl alcohol, microcrystalline wax etc. are more preferable. Inparticular, hardened castor oil, carnauba wax etc. are preferable.

When the polyglycerol fatty acid ester is used in combination withlipid, the lipid is preferably fats and oils (preferably hardened oils)and wax.

Specific combination of the polyglycerol fatty acid ester and the lipidincludes e.g. combinations of at least one member selected from behenicacid hexa(tetra)glyceride, behenic acid dodeca(deca)glyceride, behenicacid octa(hexa)glyceride, stearic acid penta(tetra)glyceride and stearicacid penta(hexa)glyceride and at least one member selected from hardenedcastor oil, carnauba wax and microcrystalline wax.

When the polyglycerol fatty acid ester is used in combination with thelipid, the content of the two components in the matrix adhering to thenasal mucosa, or the ratio thereof to the drug exerting its effect inthe brain, shall be identical with the content or the ratio of thepolyglycerol fatty acid ester when used singly.

In this invention, the viscogenic substance means a pharmaceuticallyacceptable substance which is rendered viscous with water to showadhesion to the nasal mucosa. In particular, a substance swelling withwater and imparted with significantly increased viscosity with water ispreferable. The viscogenic substance includes e.g. a polymer, anaturally occurring viscogenic substance, etc.

2% aqueous solution of said polymer at 20° C. has a viscosity of about 3to about 50000 cps, preferably about 10 to about 30000 cps and morepreferably about 15 to about 30000 cps. In the case of a polymerthickening upon neutralization, 0.2% neutralized solution thereof at 20°C. has a viscosity of about 100 to about 500000 cps, preferably about100 to about 200000 cps and more preferably about 1500 to about 100000cps.

The viscosity of the viscogenic substance shall be determined at 20° C.with a Brookfield viscometer.

The polymer is preferably an acidic polymer, and the acidic polymerincludes polymers having carboxyl groups, sulfo groups or salts thereof.In particular, the polymer having carboxyl groups or salts thereof ispreferable.

The polymer having carboxyl groups or salts thereof includes e.g.acrylate type polymers (including copolymers) comprising acrylic acid asa constituent monomer, or salts thereof. The salts include monovalentmetal salts such as sodium and potassium salts; and divalent metal saltssuch as magnesium and calcium salts. The acrylate type polymer or saltsthereof include polymers containing about 58 to about 63% by weight ofcarboxyl groups and having molecular weights of about 200,000 to6,000,000, preferably 1,000,000 to 6,000,000, more preferably 1,000,000to 5,000,000. Preferable acrylate type polymers and salts thereofinclude acrylate homopolymers and salts thereof. The acrylate polymercontaining about 58 to about 63% by weight of carboxyl groups isdescribed as carboxy vinyl polymer in Non-Pharmaceutical IngredientStandards in Japanese Pharmacopoeia (October, 1986). Examples of saidpolymer include e.g. Carbomer (trade name: Carbopol produced by The B.F. Goodrich Company) 940, 934, 934P, 941, 1342, 974P (NF XVIII) etc.;HIVISWAKO 103, 104, 105 (trade name, produced by Wako Pure ChemicalIndustries, Ltd.), NOVEON AA1 (trade name, produced by The B.F. GoodrichCompany), calcium polycarbofil (USP XXIII) etc.

The naturally occurring viscogenic substance includes e.g. mucin, agar,gelatin, pectin, carrageenan, sodium alginate, locust bean gum, xanthanegum, tragacanth gum, gum arabic, chitosan, pullulan, waxy starch,sucralfate, cellulose and derivatives thereof (for example,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulosesulfate etc.). In particular, hydroxypropyl cellulose,hydroxypropylmethyl cellulose etc. are preferable.

Two or more naturally occurring viscogenic substances described abovemay be mixed and used in an arbitrary ratio.

The viscogenic substance is preferably an acrylate type polymer or asalt thereof.

The content of the viscogenic substance in the matrix adhering to thenasal mucosa is for example about 0.005 to about 99% by weight,preferably about 0.5 to about 45% by weight and more preferably about 4to about 30% by weight.

The matrix adhering to the nasal mucosa according to this invention mayfurther contain a swelling agent for the viscogenic substance. Theswelling agent for the viscogenic substance refers to a pharmaceuticallyacceptable substance swelling the viscogenic substance or promotingswelling of the viscogenic substance with water. The swelling agent canbe used to provide the matrix adhering to the nasal mucosa which isexcellent in adhesion to the nasal mucosa and can be retained in thenasal mucosa for a prolonged period of time.

The swelling agent for the viscogenic substance includes e.g. curdlanand low-substituted hydroxypropylmethyl cellulose.

Curdlan is a linear water-insoluble polysaccharide (β-1,3-glucan)produced by a microorganism (Alcaligenes faecalis var. myxogenes), andparticularly curdlan N (food additive) can be used preferably.

The low-substituted hydroxypropyl cellulose (Japanese Pharmacopoeia,12th revised edition) is prescribed as follows: alcohol groups on thecellulose have been replaced by hydroxypropoxy groups, and the contentof the hydroxypropyl groups (% by weight) is 5.0 to 16.0%. It ispossible to use a wide variety of such cellulose having a content ofsubstituent groups in this range and a varying particle size, forexample, LH-11 (hydroxypropoxyl group content: 10.0 to 13.0% by weight;particle size: 98% by weight or more particles pass through a screen of150 μm in mesh size, and 0.5% by weight or less particles are on ascreen of 180 μm in mesh size), LH-20 (hydroxypropoxyl group content:13.0 to 16.0% by weight; particle size: 90% by weight or more passthrough a screen of 75 μm, and 1.0% by weight or less are on a screen of106 μm), LH-21 (hydroxypropoxyl group content: 10.0 to 13.0% by weight;particle size: 90% by weight or more pass through a screen of 75 μm, and1.0% by weight or less are on a screen of 106 μm), LH-22(hydroxypropoxyl group content: 7.0 to 10.0% by weight; particle size:90% by weight or more pass through a screen of 75 μm, and 1.0% by weightor less are on a screen of 106 μm) and LH-31 (hydroxypropoxyl groupcontent: 10.0 to 13.0% by weight; average particle diameter 30 μm orless; particle size: 50% by weight or more pass through a screen of 45μm, and 5.0% by weight or less are on a screen of 75 μm). In particular,LH-22 and LH-31 are preferable.

The content of the swelling agent for the viscogenic substance in thematrix adhering to the nasal mucosa is for example about 0.5 to about50% by weight, preferably about 1 to about 50% by weight and morepreferably about 1 to about 30% by weight.

In this invention, the drug exerting its effect in the brain (alsoreferred simply to hereinafter as the drug) includes e.g. the followingcompounds, hormones, peptides, proteins etc. acting via the nervecenter: antiinflammatory agents such naproxen sodium, isopropylantipyrine, ibuprofen, ketoprofen and diclofenac; sympathetic nervousagonists such as ephedrine hydrochloride, salbutamol sulfate, andphenylpropanolamine hydrochloride; antihistamines such aschlorpheniramine maleate, diphenhydramine hydrochloride, and clemastinefumarate; antibiotics such as amoxicillin, cephalexin, clarisromycin andchloxasilin sodium antitumor agents such as fluorouracil, cisplatin andmethotrexate; anti-epileptic agents such as phenytoin sodium,ethosuximide, and sodium valproate; choline agonists such as bethanecholhydrochloride, neostigmine bromide, and carbachol; opioid compounds suchas morphine hydrochloride, morphine sulfate, oxycodone, codeine,buprenorphine, and fentanyl; sedative-hypnotic agents or antianxietyagents such as melatonin, diazepam, and chlordiazepoxide; antidepressantagents such as fluoxetin, sertraline, paroxetine, Venlafaxine,nefazodone, reboxetine, imipramine hydrochloride and duloxetine;anesthetics such as droperidol and halothane; anti-Parkinson drugs suchas dopamine, L-dopa, and apomorphine; drugs for mind and nerves, such ashaloperidol, prochlorperazin; cerebral circulation-ameliorating drugssuch as vinpocetine; drugs for treating schizophrenia, such asolanzapine, risperidone, quetiapine and iloperidone; intelligenceimprovers; drugs for treating migraines, such as dihydroergotamine,sumatriptan, butrophanol, and capsaicin; skeletal muscle-relaxing drugs;agents for treating Alzheimer's disease, such as tacrine and donepezil;agents for treating alcoholism; auxiliary agents for quitting smoking;agents for treating drug abuse; vomiting-controlling drugs; drugs forthe central nervous system, such as idebenone, indeloxazinehydrochloride, bifemelane hydrochloride, protirelin tartrate, andbaclofen; neurotransmitters and related substances, such as acetylcholine, γ-aminobutyric acid, serotonin, β-endorphin,methionine-enkephalin, Substance P, glycine, glutamic acid, asparticacid, vasoactive intestinal polypeptide (VIP), epinephrine,norepinephrine and neurotensin; peptides released from the hypothalamusand involved in hormone synthesis and secretion, such asthyrotropin-releasing hormone (TRH), corticotropin-releasing hormone(CRH), luteinizing hormone-releasing hormone (LHRH),follicle-stimulating hormone-releasing hormone (FSHRH),prolactin-releasing hormone (PrRH), growth hormone-releasing hormone(GRH), somatostatin, galanin, galanin-like peptide (GALP), neuromedin U,ghrelin, apelin, urotensin II, orexin, and their related compounds suchas agonists and antagonists, for example leuprorelin; pituitary hormonessuch as thyroid-stimulating hormone (TSH), adrenocorticotropic hormone(ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH),prolactin (PRL), growth hormone (GH), vasopressin, oxytocin andneuropeptide Y; thyroid hormone; parathyroid hormone (PTH); saccharidemetabolism-related hormones such as insulin and glucagon;adrenocorticotropic medulla-related peptides such as angiotensin,dehydroepiandrosterone; alimentary canal hormones such as gastrin,secretin, cholecystokinin and motilin; neuropeptides involved inappetite regulation, such as leptin, melanin concentrating hormone(MCH), opioid, cholecystokinin, bombesin, and their related compoundssuch as agonists and antagonists; and compounds related to instinctivebehaviors and body temperature.

Out of these drugs, those drugs which upon administration into bloodvessels, digestive tracts, lungs, skin etc., undergo significantrestriction of transfer thereof to the brain because of theirdegradation with gastric acid or enzyme, metabolism by the initialpassage effect, or the blood-brain barrier (that is, drugs hardlytransferring into the brain), or exhibit side-effects because of anincrease in their blood levels can be effectively used in the matrixadhering to the nasal mucosa according to this invention.

In the matrix adhering to the nasal mucosa, the content of the drugexerting its effect in the brain is for example about 0.005 to about 95%by weight, preferably about 0.1 to about 90% by weight, more preferablyabout 0.1 to about 50% by weight.

The drug exerting its effect in the brain is preferably is asedative-hypnotic agent, an anti-anxiety agent, an antidepressant agentor an agent for treating Alzheimer's disease.

For example, such drugs are preferably compounds having a melatoninreceptor agonist action. The compounds having a melatonin receptoragonist action are not particularly limited insofar as they have suchaction, and for example, such melatonin agonists or antagonists thereofinclude:

(1) compounds described in EP-A-578620, represented by the formula:

(2) a compound described in U.S. Pat. No. 411,675, represented by theformula:

(3) a compound described in JP-A 7-048331 (EP-A-447285), represented bythe formula:

(4) a compound described in FR-014630, represented by the formula:

(5) a compound described in EP-A-591057, represented by the formula:

(6) compounds described in EP-A-527687, represented by the formulae:

(7) compounds described in EP-A-506539, represented by the formulae:

(8) compounds described in JP-A 7-196493 or JP-A 63-196563, representedby the formula:

wherein R¹ is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; R² is hydrogen orC₁₋₄ alkyl; R³ is hydrogen, C₁₋₄ alkyl, phenyl or substituted phenyl; R⁴is hydrogen, haloacetyl, C₁₋₅ alkanoyl, benzoyl, or halo- ormethyl-substituted benzoyl; each of R⁵ and R⁶ is hydrogen or halo; andR⁷ is hydrogen or C₁₋₄ alkyl, provided that when R³, R⁴ and R⁵ each arehydrogen, R² is C₁₋₄ alkyl;

or salts thereof, and

particularly a compound (LY156735) represented by the formula:

(9) compounds described in WO 97/43272, represented by the formula:

wherein R¹ and R² are the same or different and represent hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl or aryl; R³ and R⁴ are the same or different andrepresent hydrogen, halogen, C₁₋₆ alkyl or substituted aryl; R⁵ ishydrogen or C₁₋₆ alkyl; n is 0, 1 or 2; and m is 1, 2, 3 or 4;

is a single or double bond,

or salts thereof, and

particularly a compound represented by the formula:

(10) compounds described in WO 98/25606, represented by the formula:

wherein each of Q¹ and Q² is hydrogen or halogen; X is CH₂, CH oroxygen; Y is CR³, CR³R⁴ or (CH₂) n (n=1-4); Z is CH₂, CH or oxygen; R ishydrogen, halogen or C₁₋₄ alkyl; m is 1 or 2; R¹ is C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₃ haloalkyl, C₁₋₆ alkylamino, C₂₋₆ alkenyl, C₁₋₄ alkoxy(C₁₋₄) alkyl, C₁₋₄ alkylthio (C₁₋₄) alkyl or trifluoromethyl alkyl; R²is hydrogen or C₁₋₄ alkyl; and each of R³ and R⁴ is hydrogen or C₁₋₄alkyl,

or salts thereof, and

particularly a compound represented by the formula:

(11) compounds described in JP-A 9-507057, represented by the formula:

wherein R¹ is hydrogen, halogen or C₁₋₆ alkyl; R² is a group of theformula —CR³R⁴(CH₂)_(p)NR⁵COR⁶; R³, R⁴ and R⁵ may be the same ordifferent and represent hydrogen or C₁₋₆ alkyl; R⁶ is C₁₋₆ alkyl or C₃₋₇cycloalkyl; n is an integer of 2, 3 or 4; and p is an integer of 1, 2, 3or 4;

or salts thereof, and

particularly a compound represented by the formula:

(12) compounds described in WO 97/32871, represented by the formula:

wherein R¹ is a hydrocarbon group which may have a substituent group, anamino group which may have a substituent group or a heterocyclic groupwhich may have a substituent group,

R² is a hydrogen atom or a hydrocarbon group which may have asubstituent group,

R³ is a hydrogen atom, a hydrocarbon group which may have a substituentgroup or a heterocyclic group which may have a substituent group,

X is CHR⁴, NR⁴, O or S whereupon R⁴ represents a hydrogen atom or ahydrocarbon group which may have a substituent group,

Y is C, CH or N provided that when X represents CH₂, Y is C or CH,

is a single or double bond,

ring A is a 5- to 7-memberred, oxygen atom-containing heterocyclic ringwhich may have a substituent group,

ring B is a benzene ring which may have a substituent group, and

m is an integer of 1 to 4;

or salts thereof.

In particular, Compound (I) having high affinity for melatonin receptorsand high selectivity particularly for ML₁ receptor is preferable.

Compound (I) is preferably a compound represented by the formula:

wherein R represents a C₁₋₆ alkyl group (methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.),and specifically Compound (I) is preferably(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide or (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl] acetamide.

In this specification, the matrix means a system where the ingredientsconstituting the matrix have been uniformly dispersed, and is clearlydistinguished from a system where the ingredients have been topically orunevenly distributed or have formed a layer, or from an emulsion or asimple mixture of the ingredients.

That is, in the matrix adhering to the nasal mucosa according to thisinvention, the ingredients, that is, “the polyglycerol fatty acidester”, “the drug exerting its effect in the brain” and “the viscogenicsubstance” have been uniformly dispersed. Further, when the matrixfurther contains “the lipid” and “the swelling agent for the viscogenicsubstance”, the lipid and the swelling agent have also been uniformlydispersed.

The matrix adhering to the nasal mucosa according to this invention isexcellent in adhesion to the nasal mucosa and capable of releasing “thedrug exerting its effect in the brain” continuously at a predeterminedrate.

The particle diameter of the matrix is preferably about 0.1 to about1500 μm, more preferably about 0.1 to about 100 μm and most preferablyabout 5 to about 50 μm.

The matrix adhering to the nasal mucosa according to this invention isproduced by uniformly dispersing e.g. the constituent ingredients, thatis, “the polyglycerol fatty acid ester”, “the drug exerting its effectin the brain” and “the viscogenic substance”. When the matrix furthercontains “the lipid” and “the swelling agent for the viscogenicsubstance”, the lipid and the swelling agent are also disperseduniformly.

For example, said matrix is produced by melting the polyglycerol fattyacid ester by heating it at the melting point or more, then adding thedrug or the viscogenic substance thereto simultaneously or separatelyand cooling the resulting mixture. When the lipid is used, the lipid isused in the same manner as for the polyglycerol fatty acid ester, andwhen the swelling agent for the viscogenic substance is used, theswelling agent is used in the same manner as for the viscogenicsubstance.

In this case, heating temperature is for example about 40 to about 150°C., preferably about 50 to about 110° C., and more preferably about 50to about 90° C.

The heating and dispersion step described above is conducted using e.g.a conventional granulator, and the cooling step is conducted by e.g.spray cooling. This spray cooling is conducted for example by spraychilling, and in this case, a solid preparation (for example, finelydivided particles) is obtained.

Spray chilling is conducted by dropping a mixture consisting of thepolyglycerol fatty acid ester, the drug and the viscogenic substance ata predetermined flow rate onto a high-speed rotating disk. The rotatingdisk used may be a smooth disk (e.g. an aluminum disk) having a diameterof 5 to 100 cm, preferably 10 to 20 cm. The rotational speed of therotating disk is for example 10 to 25000 rpm, preferably 3000 to 20000rpm, more preferably 6000 to 15000 rpm. The rate of dropping the mixtureis selected depending on the desired particle diameter, but is usuallyabout 2 to 200 g/min., preferably about 5 to about 100 g/min.

The matrix of this invention obtained by this spray chilling method isapproximately spherical. Therefore, a stable rate of releasing the drugcan be achieved, and thus spray chilling is preferable as a method ofproducing the matrix of this invention.

Alternatively, the matrix adhering to the nasal mucosa according to thisinvention can also be produced by dispersing the constituent ingredientsby kneading them in a conventional solvent (for example, methanol,acetonitrile, chloroform etc.), followed by granulation thereof.

The matrix adhering to the nasal mucosa according to this invention maybe formed into a solid preparation by coating it with a coating agentcontaining the above viscogenic substance or pharmaceutical additives.The coating agent may further contain at least one additive selectedfrom the swelling agent for the viscogenic substance, the polyglycerolfatty acid ester and a water-insoluble polymer.

The pharmaceutical additives may be those ordinarily used in the fieldof pharmaceutical manufacturing, and include e.g. excipients such aslactose, corn starch, talc, crystalline cellulose, powdery sugar,magnesium stearate, mannitol, xylitol, sorbitol, erythritol, lightsilicic anhydride, magnesium carbonate, calcium carbonate andL-cysteine; binders such as starch, sucrose, gelatin, powder of gumarabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinyl pyrrolidone, pullulan and dextrin; disintegrating agents suchas calcium carboxymethyl cellulose, low-substituted hydroxypropylcellulose, sodium croscarmellose, sodium carboxymethyl starch,hydroxypropyl starch and partially pregelatinized starch; surfactantssuch as anionic surfactants such as sodium alkyl sulfate, and nonionicsurfactants such as polyoxyethylene sorbitan fatty acid esters,polyoxyethylene fatty acid esters and polyoxyethylene castor oilderivatives; acid regulators and mucosa-protecting agents such asmagnesium hydroxide, magnesium oxide, aluminum hydroxide, aluminumsulfate, magnesium metasilicate aluminate, magnesium silicate aluminateand sucralfate; coloring agents; taste correctives; adsorbents;preservatives; swelling agents; and antistatic additives. The amount ofthese pharmaceutical additives is suitably selected in the range wherethe adhesion of the solid preparation to the nasal mucosa is notdeteriorated.

The “water-insoluble polymer” which may be added to the coating agentincludes e.g. hydroxypropylmethyl cellulose phthalate,hydroxypropylmethyl cellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate trimellitate, cellulose acetate phthalate,ethyl cellulose, aminoalkyl methacrylate copolymers [trade name:Eudragit RS-100, RL-100, RL-PO, RS-PO, RS-30D, RL-30D produced by RöhmPharma Ltd.], methacrylic acid-ethyl acrylate copolymers [trade name:Eudragit L100-55 produced by Röhm Pharma Ltd.], methacrylic acid-methylmethacrylate copolymers [trade name: Eudragit L100, S100, L30D-55,NE-30D, produced by Röhm Pharma Ltd.] and polyvinyl acetate. Two or moreof these polymers can be mixed and used in an arbitrary ratio.

The content of the viscogenic substance in the coating agent is forexample about 0.005 to about 100% by weight, preferably about 0.05 toabout 95% by weight and more preferably about 1 to about 10% by weightof the total solid content in the coating agent.

When the coating agent contains pharmaceutical additives, the content ofthe pharmaceutical additives is for example about 0.1 to about 70% byweight, preferably about 1 to about 50% by weight and more preferablyabout 20 to about 50% by weight of the total solid content in thecoating agent.

The amount of the coating agent applied is suitably selected dependingon the shape of the solid preparation, the desired adhesion to mucosae,etc. For example, when the solid preparation is in the form of granules,the amount of the coating agent applied thereon is about 0.1 to about50% by weight, preferably about 1 to about 20% by weight, relative tothe whole of the solid preparation. Further, when the solid preparationis in the form of finely divided particles, the amount of the coatingagent applied thereon is about 0.1 to about 100% by weight, preferablyabout 1 to about 50% by weight, relative to the whole of the solidpreparation.

As the coating method, it is possible to use any methods known in theart, for example pan coating, fluid coating, rolling coating etc. Whenthe coating agent is a solution or dispersion containing water or anorganic solvent, spray coating can also be used. The type of the organicsolvent is not particularly limited, and use can be made e.g. alcoholssuch as methanol, ethanol and isopropyl alcohol; ketones such asacetone; halogenated hydrocarbons such as chloroform, dichloromethaneand trichloroethane.

When the coating agent contains the polyglycerol fatty acid ester, thepolyglycerol fatty acid ester and if necessary other additives may becoated by heating and melting them, then kneading and emulsifying theresultant mixture in water, spraying the resultant emulsion onto thematrix and drying it.

Further, when the coating agent contains the polyglycerol fatty acidester, the matrix preheated with hot air in a device such as a coatingpan may be coated therewith by introducing the coating agent into thedevice and then melting and extending it on the matrix.

The temperature for coating is usually about 25 to about 60° C.,preferably about 25 to about 40° C.

The time necessary for coating is suitably selected in consideration ofthe coating method, the properties and amount of the coating agent used,and the properties of the matrix.

The solid preparation may be in any form usable as a nasal agent, andthe form of the preparation includes e.g. finely divided particles,powder and granules. In particular, finely divided particles and powderare preferable.

The particle diameters of the finely divided particles are distributedsuch that for example, 75 to 500 μm particles account for 85 weight % ormore, 500 to 850 μm particles for 5 weight % or less, 850 μm or moreparticles for 0 weight %, and 74 μm or less particles for 10 weight % orless.

The particle diameters of the powder are distributed such that forexample, 500 to 850 μm particles account for 5 weight % or less, 500 μmor less particles for 95 weight % or more, and 850 μm or more particlesfor 0 weight %.

The particle diameters of the granules are distributed such that forexample, 500 to 1410 μm particles account for 90 weight % or more, and177 μm or less particles for 5 weight % or less.

The solid preparation is preferably in a particle form, more preferablyin a spherical form. The particle diameter is selected from the rangewhere the solid preparation can be used as a nasal agent. The particlediameter of the solid preparation is preferably about 0.1 to about 1500μm, more preferably about 0.1 to about 100 μm and most preferably about5 to about 50 μm.

The most preferable form of using the matrix adhering to the nasalmucosa according to this invention is a preparation for nasaladministration (preferably a spray) obtained by encapsulating the solidpreparation (preferably finely divided particles or powder) obtained inthe manner described above, together with additives such as astabilizer, a taste corrective, a suspending agent, an emulsifier, aperfume, a dispersant and a lubricant, into a suitable vessel and thensealing the vessel. Preferably, the jetted form of the spray is forexample in the form of spray, paste, foam or powder, and the powderyform is particularly preferable.

The matrix adhering to the nasal mucosa according to this invention maybe used after it is dissolved, suspended or emulsified in an aqueoussolvent (for example, distilled water, physiological saline, Ringer'ssolution) or an oil solvent (for example, vegetable oils such as oliveoil, sesame oil, cottonseed oil and corn oil; propylene glycol etc.).

The matrix adhering to the nasal mucosa according to this invention islow-toxic and safely administered via the nose into mammals (forexample, humans, monkeys, dogs, cats, rabbits, cattle, horses, goats,rats, mice etc.).

The dose of the matrix adhering to the nasal mucosa according to thisinvention may be suitably determined in consideration of the type of thedrug, the subject of administration, etc. For example, when the matrixadhering to the nasal mucosa according to this invention is administeredas a spray into an adult (weighing about 50 kg) for the purpose ofpreventing and treating diseases such as encephalomyelitis etc., thedaily dose of the matrix adhering to the nasal mucosa is usually about 1to about 2000 mg and preferably about 20 to about 600 mg, morepreferably about 20 to about 200 mg (or about 1 to about 1500 mg,preferably about 20 to about 500 mg and more preferably about 20 to 150mg in terms of the drug). This dose may be administered in one to threeportions.

The diseases to which the matrix adhering to the nasal mucosa accordingto this invention is applied are selected depending on the type of “thedrug exerting its effect in the brain”.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, this invention is described in more detail by reference tothe Examples, which however are not intended to limit this invention.

EXAMPLES Example 1

7.0 g behenic acid hexa(tetra)glyceride (trade name: HB-310, produced bySakamoto Yakuhin Kogyo Co., Ltd.) and 1.0 g hardened sesame oil [tradename: Lovely Wax 101 (LW-101) produced by Freund Industrial Co., Ltd.]were weighed and melted by heating at 84° C. To the resulting moltenmixture were added 1.0 g cephalexin and 1.0 g acrylate type polymer(trade name: HIVISWAKO 104 produced by Wako Pure Chemical Industries,Ltd.) in succession, and the mixture was kept at 84° C. for 15 minutesunder stirring. The resulting molten mixture was dropped at a rate of 10g/min. onto an aluminum disk of 15 cm in diameter rotating at 9000 rpm,to give 6.8 g powder (spherical particles) having a diameter of about 50μm.

Example 2

8.0 g behenic acid hexa(tetra)glyceride (trade name: HB-310, produced bySakamoto Yakuhin Co., Ltd.) was weighed and melted by heating at 84° C.1.0 g (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide (Compound A) and 1.0 g acrylate type polymer (trade name:HIVISWAKO 104, Wako Pure Chemical Industries, Ltd.) were added theretoin succession, and the mixture was dispersed by keeping it at 84° C. forabout 1 hour under stirring. The resulting molten mixture was dropped ata rate of 10 g/min. onto an aluminum disk of 15 cm in diameter rotatingat 9000 rpm, to give about 50 μm spherical particles.

Experimental Example 1

10 mg of the particles (cephalexin content: 1 mg) obtained in Example 1was charged into a polyethylene tube having an inner diameter of 0.58 mmand an outer diameter of 0.965 mm [trade name: PE50; produced by NipponBecton Dickinson Ltd.], and the total amount of the powder in the tubewas administered into the nasal cavity of each SD rat (9- to 10-week-oldmale) under anesthesia with ether.

Separately, 20 μl aqueous suspension of cephalexin (cephalexin content:1 mg) was administered into the nasal cavity of each SD rat (9- to10-week-old male) under anesthesia with ether, and this rat was used asthe control.

One hour after administration, the concentrations of cephalexin inplasma and cerebrospinal fluid were measured by HPLC. The results areshown in Table 1.

Each concentration in the table shows an average concentration obtainedusing 4 rats.

TABLE 1 Concentration in Concentration in cerebrospinal plasma (μg/ml)fluid (μg/ml) Suspension 0.89 0.037 Powder in 0.77 0.326 Example 1

As shown in Table 1, when the preparation of this invention wasadministered via the nose into the rat, the concentration of the drug inthe cerebrospinal fluid was significantly higher than by the controlsuspension. That is, transfer of the drug into the brain was improved bythe preparation of this invention.

Experimental Example 2

The particles obtained in Example 2 was charged into a polyethylene tubehaving an inner diameter of 0.58 mm and an outer diameter of 0.965 mm[trade name: PE50, produced by Nippon Becton Dickinson Ltd.], and thenadministered in a dose of 3 mg/rat into the nasal cavity of each SD malerat under anesthesia with ether. As the control, 25 μl suspension ofCompound A was administered into the nasal cavity of each rat. Theconcentration of the drug in plasma for 2 hours after administration wasmeasured, and its AUC was calculated. Further, the concentration of thedrug in cerebrospinal fluid at 2 hours after administration was measuredas an indicator of transfer of the drug into the brain. The results areshown in Table 2.

TABLE 2 Concentration in cerebrospinal AUC_(0-2h) (μg/ml) fluid (ng/ml)Suspension 1.57  9 Particles in 1.78 54 Example 2

As shown in Table 2, when the preparation of this invention wasadministered via the nose into the rat, the concentration of the drug inthe cerebrospinal fluid was significantly higher than by the controlsuspension. That is, transfer of the drug into the brain was improved bythe preparation of this invention.

INDUSTRIAL APPLICABILITY

When “the drug exerting its effect in the brain” is orally administered,transfer of said drug into the brain is significantly restricted due todegradation with gastric acid or enzyme, metabolism by the first passeffect, etc. Further, when “the drug exerting its effect in the brain”is subcutaneously or intravenously administered, transfer of said druginto the brain is significantly restricted by the blood-brain barrier.

By using the matrix adhering to the nasal mucosa according to thisinvention, “the drug exerting its effect in the brain” in said matrixcan, without undergoing the above restriction, be transferred directlyfrom the nasal cavity via the cerebrospinal fluid to brain tissues, thusachieving extremely high transfer of said drug into the brain.

Furthermore, the matrix adhering to the nasal mucosa according to thisinvention is excellent in adhesion to the nasal mucosa and can beretained on the nasal mucosa for a prolonged period of time, thusallowing “the drug exerting its effect in the brain” to be suppliedcontinuously into the brain for a prolonged period of time.

What is claimed is:
 1. A matrix adhering to the nasal mucosa whichallows improved transfer into the brain of a drug exerting its effect inthe brain, which comprises a polyglycerol fatty acid ester, the drugexerting its effect in the brain, and a viscogenic substance, whereinthe drug exerting its effect in the brain is(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide.
 2. A matrix adhering to the nasal mucosa which allowsimproved transfer into the brain of a drug exerting its effect in thebrain, which comprises a polyglycerol fatty acid ester, the drugexerting its effect in the brain, and a viscogenic substance, whereinthe drug exerting its effect in the brain is(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]acetamide.